Parkinson's disease (PD) is one of the most common adult neurodegenerative disorders, affecting over 1 million people in North America and the European Union. Although transient symptomatic improvement can be obtained with currently available pharmacotherapies, functional ability deteriorates over time. Development of therapies that can slow or forestall the progression of PD would fill a major unmet medical need of these patients. As a first step in identifying such therapies, the NINDS Exploratory Trials in Parkinson's disease (NET-PD) network successfully completed futility studies, which identified creatine as a potential agent to slow clinical decline in PD. The NET-PD network is now conducting a large, long-term. Phase 3 trial (known as LS1) comparing creatine to placebo. Our site has been part of the NET-PD network since its inception and we have participated in all of the NET-PD activities. Our site, a consortium of sites at Thomas Jefferson University and at Lankenau Medical Center, has enrolled 50 subjects into the LS1 study (7' highest enrollment of all LS1 sites) and has an excellent record or subject retention and follow-up. During the renewal period covered in the current application, the following specific aims for continuation and completion of the LS1 study, are proposed: Aim 1 Retain current subjects and complete follow-up and of enrolled participants in order to test the primary hypothesis that daily administration o creatine (10gm/day) is more effective than placebo in slowing clinical decline in PD between baseline and the 5 year follow-up visit, against the background of dopaminergic therapy and best PD care; Aim 2 Perform secondary efficacy analyses to evaluate the effect of creatine on individual PD clinical measures collected over the 5-8 years of study participation, as well as analyses of overall safety and tolerability; Aim 3 The extent to which the scales for Outcomes of Parkinson's disease-cognition (SCOPA-COG) is sensitive to detect cognitive changes in a relatively early cohort of PD patients will be examined along with the sensitivity of this battery or assessing longitudinal changes in PD patients. The PI will work with the Statistical Coordination Center and the Cognition Writing Group (of which he has been the head) to achieve this aim. In addition, we will contribute to the analysis and writing of a manuscript examining potential clinical predictors of cognitive function in early, treated PD, using demographic, concomitant medication, and comorbid disease information at baseline along with measurements from the SCOPA-COG and Symbol Digit Modalities Test (SDMT), the principal tests of cognitive function in LS1. RELEVANCE (See Instructions): The accumulated disability that PD causes is a major source of diminished quality of life and increased health care costs. Despite the advances in our understanding of the pathophysiology in PD, there are no current therapies that slow the inexorable clinical decline. LSI will help to determine if creatine can slow clinical decline and provide better information on the course of early PD than is currently available. Disclaimer: Please note that the following critiques were prepared by the reviewers prior to the Study Section meeting and are provided in an essentially unedited form. While there is opportunity for the reviewers to update or revise their written evaluation, based upon the group's discussion, there is no guarantee that individual critiques have been updated subsequent to the discussion at the meeting. Therefore, the critiques may not fully reflect the final opinions of th individual reviewers at the close of group discussion or the final majority opinion of the group. Thus the Resume and Summary of Discussion is the final word on what the reviewers actually considered critical at the meeting.